A growing body of epidemiological and laboratory evidence suggests a connection between environmental exposures to chemicals, including insecticides, with development of obesity and type 2 diabetes. However there is a paucity of investigation into the mechanism(s) by which these insecticides influence lipid and glucose metabolisms contributing to weight gain, development of type 2 diabetes, and related chronic disease conditions. The long-term goal is to elucidate the underlying causes of obesity and type 2 diabetes. The specific objective of this project is to determine the potential contribution of permethrin (a pyrethroid insecticide) to development of obesity and type 2 diabetes. The central hypothesis is exposure to permethrin will alter lipid metabolism and glucose homeostasis along with dietary fat, resulting in potentiated weight gain and impaired insulin responses. The rationale of this proposed research is: that by understanding biochemical mechanisms by which exposure to environmental contaminants (permethrin in this case) may result in development of obesity and type 2 diabetes, more efficient prevention and/or treatment strategies for these and related pathologies will be available now and in the future. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing knowledge that will potentially help to reduce human diseases. Based on preliminary data, the hypothesis will be tested by pursuing the following specific aim: Determine mechanisms of permethrin on development of obesity and type 2 diabetes. In Objective 1, effects of permethrin on altered lipid metabolisms will be tested using 3T3-L1 adipocytes under the hypothesis that permethrin promotes adipogenesis by modulating AMP-activated protein kinase (AMPK) via a calcium-dependent mechanism. In Objective 2, the role of permethrin on impaired glucose homeostasis will be tested using C2C12 myotubes under the hypothesis that permethrin modulates insulin-receptor substrate-1 (IRS-1) via a calcium-mediated mechanism. In Objective 3, effects of permethrin on development of obesity and type 2 diabetes will be determined in C57BL/6J mice model under the hypotheses that [i] exposure to permethrin potentiates weight gain and the development of insulin resistance in a dose- and sex-dependent manner and [ii] interactions between permethrin and dietary fat will influence weight gain and development of insulin-resistance. The innovative aspect of this proposed research is targeting permethrin, a pyrethroid insecticide, as a potential contributing factor for obesity and type 2 diabetes. Of particular interest, this proposed research includes experiments to determine the potential interaction between permethrin exposure and dietary fat. The results from the proposed research will be significant as the outcome will provide a clearer understanding of how exposure to environmental contaminants may contribute to the development of obesity and type 2 diabetes.